This multidisciplinary program focuses on the molecular mechanisms whereby oncoproteins, tyrosine kinase receptors and tumor suppressor genes regulate cell survival. The program has four projects. There is also a request for an administrative and a nucleic acids core component.The investigators intend to study: i) the mechanisms and the significance of enhanced MDM2 levels in BCR/ABL-expressing cells and BCR/ABL-dependent leukemogenesis, the mechanisms whereby BCR/ABL suppresses C/EBPalpha expression and the biological consequences of restoring C/EBPalpha expression in BCR/ABL cells; ii) the mechanisms whereby the IGF-1 receptor promotes the localization of IRS-1 in the nucleus, the regulation of IRS-1 expression and promoter activity by IGF-1R and STAT-3, and the role of IRS-1, Id2, pRb, and STAT-3 in IGF-1-mediated regulation of apoptosis, proliferation and differentiation; iii) the pro-apoptotic effects involved in tumor suppression by the Fhit gene and the role of Fhit loss of function in tumorigenesis; iv) the role of the newly identified mitochondrial serine proteinase, Omi, in caspase-dependent and caspase-independent apoptosis and the involvement of the ER-localized GSPT-1 protein in the ER stress-induced apoptosis. The long-term objective of this Program Project is to utilize this information as a molecular basis for devising more rational approaches to anti-cancer therapies.